Role of sigma receptors in ethanol reinforcement

摘要：该申请为瓦伦蒂娜·萨比诺博士提出了一份职业发展计划 受过药理学训练的博士后致力于乙醇成瘾的研究生涯 去了解它的分子基础。申请者将由George Koob博士指导 酒精中毒的神经科学方法和动物模型，由Pietro Sanna博士在 免疫组织化学和分子技术。该项目将在斯克里普斯研究中心进行 圣地亚哥丰富的神经科学社区的研究所，关注独特的哺乳动物Sigma受体 调节其他神经递质系统的结合位点，在边缘脑中大量表达 结构。药理学研究表明，Sigma受体调节可卡因和 冰毒。最近，Sigma受体也被认为可以调节血管紧张素转换酶的兴奋特性。 乙醇，与人类酒精中毒西格玛受体多态的研究结果一致。直到最近， 然而，对sigma受体系统的理解由于无法获得特定的， 亚型-选择性配体或缺乏Sigma受体亚型的突变小鼠模型。此外， Sigma受体在乙醇自愿摄入或自我给药中的作用尚不清楚。现在 多学科应用使用行为、药理学和分子技术来确定 不同亚型特异性的Sigma受体对乙醇奖赏和增强的调节作用 过度消费酒精的模型。两种过量酒精摄入量的模型将被具体研究 目标1和3--基因选择的偏爱酒精的大鼠和依赖的退出的近交系大鼠 在慢性、间歇性接触乙醇蒸气期间，强调积极和消极的强化 乙醇的性质。乙醇自身给药将受到药物调节(在 特定目的1)，通过给药新的a受体配体，以及分子上(在特定目的2中)， 通过使用O-1受体KO小鼠。长期接触乙醇和先天酒精的影响 乙醇对离散边缘脑区o受体蛋白表达的偏好将在 具体目标3.相关性：该项目将确定 酒精滥用和依赖的调节受体系统功能不足。

Summary: The application proposes a career development plan for Dr. Valentina Sabino, a pharmacologically-trained post-doctoral fellow committed to a research career in ethanol addiction aimed towards understand its molecular basis. The applicant will be mentored by Dr. George Koob in behavioral neuroscience methods and animal models of alcoholism and co-mentored by Dr. Pietro Sanna in immunohistochemical and molecular techniques. The project, to be conducted at The Scripps Research Institute in the rich neuroscience community of San Diego, concerns sigma receptors, unique mammalian binding sites that modulate other neurotransmitter systems and which are richly expressed in limbic brain structures. Pharmacological studies indicate that sigma receptors modulate actions of cocaine and methamphetamine. Recently, sigma receptors also have been proposed to modulate motivating properties of ethanol, consistent with findings of sigma receptor polymorphisms in human alcoholism. Until very recently, however, the understanding of sigma receptor systems had been hampered by the unavailability of specific, subtype-selective ligands or of mutant mouse models that lack sigma receptor subtypes. Furthermore, the role of sigma receptors in voluntary intake or self-administration of ethanol are unknown. The present multipdisciplinary application uses behavioral, pharmacologic, and molecular techniques to determine the modulatory role of sigma receptorswith subtype specificity on ethanol reward and reinforcementin distinct models of excessive ethanol consumption. Two models of excess ethanol intake will be studied in Specific Aims 1 and 3 -- genetically selected alcohol-preferring rats and withdrawn outbred rats made dependent during chronic, intermittent exposure to ethanol vapor, emphasizing positive and negative reinforcing properties of ethanol, respectively. Ethanol self-administration will be pharmacologically modulated (in Specific Aim 1), through the administration of novel a receptor ligands, and molecularly (in Specific Aim 2), through the use of o-1 receptor KO mice. The impact of chronic exposure to ethanol and of innate preference for ethanol on o receptor protein expression in discrete limbic brain regions will be investigated in Specific Aim 3. Relevance: The project will define the physiologic and potential therapeutic relevance of an undercharacterized modulatory receptor system for alcohol abuse and dependence.